Autism spectrum disorders (ASD) are neurodevelopmental abnormalities characterized by impairments in two core domains: social interaction/communication and repetitive, stereotyped behaviors. Accumulating evidence suggests that mutations in genes essential for synaptic function, such as the synaptic adhesion molecules neurexin and neuroligin, are associated with ASD. While human genetic studies have revealed a growing number of candidate genes implicated in ASD it has been difficult to investigate autism pathophysiology due to the polygenic nature of the disease. One potential approach is to identify specific neural circuits that mediate ASD-associated behaviors. Recently, our lab has identified a nucleus accumbens circuit defect that drives ASD-related motor behaviors, by employing the accelerating rotating rod (rotarod) paradigm as a measurement of the formation of repetitive motor routines. We demonstrated that learning in this task was correlated with decreased variability of multiple behavioral measures, including vertical location of step placement, the length of each step and the temporal interval between steps. Furthermore, Neuroligin-3 knockout (KO) mice had an enhancement in rotarod learning that was driven by a more rapid and lasting ?stereotyping? of all three behavioral measures. At the physiological level, we found that decreased synaptic inhibition onto nucleus accumbens D1R+ MSNs in Neuroligin-3 KOs could in part drive formation of stereotyped behavior in the rotarod paradigm. As the enhanced rotarod learning phenotype has recently been observed across multiple genetic mouse models for ASD, I will employ this task as a behavioral ?endophenotype? in attempts to uncover common neural circuit abnormalities. I hypothesize that impaired synaptic transmission in the nucleus accumbens is a recurring neural circuit defect that mediates enhanced stereotyped motor output. In this proposal, I will be examining alterations of nucleus accumbens synaptic function and behavioral output in an ASD-associated mouse model harboring mutations in Neurexin-1?, a synaptic adhesion protein involved in synapse organization and function. In Aim 1, changes in nucleus accumbens synaptic activity that may contribute to ASD-related motor abnormalities will be probed in striatal acute slice preparations via whole-cell electrophysiological recordings. In Aim 2, I will employ circuit?specific genetic loss-of-function, together with in vivo chemogenetic manipulations to put our electrophysiological findings into a behaviorally relevant neural circuit context. Together, these aims will provide a robust training program while exploring novel neural circuit changes that may drive ASD-relevant behaviors.